A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice

Abstract

Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E2 (PGE2). PGE2 induction requires a nuclear factor κB–independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not Rela or Tgfb1, in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (TH1)/TH17 infiltration and aggravated colitis development. PGE2 administration ameliorated colitis in mouse models with defective PGE2 production but not in animals with normal PGE2 induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE2 biosynthesis, in inflamed tissues, and especially in colon Vimentin+Twist2+ stromal cells, in about 60% of patients with active Crohn’s disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE2 production.

Integrated Analysis Reveals the Targets and Mechanisms in Immunosuppressive Effect of Mesalazine on Ulcerative Colitis

“…PTGS2, alternatively termed COX-2, is an inflammatory enzyme associated with intestinal inflammatory disease like IBD ( 34 ). A previous clinical study has demonstrated a negative correlation between the protein levels of COX-2 and the disease severity of IBD ( 35 ). A review has also suggested that COX-2 can cause the clinical manifestations of a bacterial infection, including inflammation and septic shock ( 36 ).…”

Moringa oleifera Lam. Peptide Remodels Intestinal Mucosal Barrier by Inhibiting JAK-STAT Activation and Modulating Gut Microbiota in Colitis

“…Recent epidemiological statistics indicate that the incidence of UC continues to increase worldwide, now affecting 0.3% of the global population (28). Therefore, it is particularly urgent to develop natural medicines with low side effects and proven safety.…”

Sprayable nanomicelle hydrogels and inflammatory bowel disease patient cell chips for development of intestinal lesion-specific therapy

“…However, this signaling change may result in other unexpected effects such as anti-angiogenesis and anti-tumorigenesis, as was reported in a previous study [ 1 ], and should be investigated in greater detail in the future. In addition, the DSS was used to produce a mouse IBD model following previous studies [ 30 ]. Other reagents such as polyinosinic-polycytidylic acid and 2,4,6-trinitrobenzene sulfonic acid could be used to exert the same pathogenic effects and thereby produce rodent IBD models [ 31 , 32 ].…”